New anticoagulant drugs for treatment of venous thromboembolism and stroke prevention in atrial fibrillation

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1 Review doi: /j x New anticoagulant drugs for treatment of venous thromboembolism and stroke prevention in atrial fibrillation A. Tripodi 1 & G. Palareti 2 From the 1 Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Internal Medicine, IRCCS Cà Granda Maggiore Hospital Foundation and Università degli Studi di Milano, Milano, Italy; and 2 Divsion of Angiology and Blood Coagulation, S.Orsola-Malpighi University Hospital, Bologna, Italy Abstract. Tripodi A, Palareti G (IRCCS Cà Granda Maggiore Hospital Foundation and Università degli Studi di Milano, Milano, Italy; S.Orsola-Malpighi University Hospital, Bologna, Italy). New anticoagulant drugs for treatment of venous thromboembolism and stroke prevention in atrial fibrillation (Review). J Intern Med 2012; 271: Venous thromboembolism (including deep vein thrombosis and pulmonary embolism) and atrial fibrillation are common conditions in Western countries. The mainstay of treatment and prevention for these diseases is fast-acting anticoagulant drugs such as heparins and vitamin K antagonists. The use of these drugs is, however, complex and demanding for both patients and physicians. Recently, new antithrombotic drugs that act directly by inhibiting activated coagulation factors such as factor X or thrombin have been developed and investigated in phase III clinical trials. The aim of this article is to review: (i) the need to develop new drugs; (ii) their efficacy safety as demonstrated in clinical trials; (iii) the need for laboratory monitoring and (iv) the direction towards the use of these new drugs in the real-life clinical situation. Introduction Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), occurs frequently in Western countries, with an estimated incidence of about 1.5 per 1000 inhabitants per year [1]. DVT may progress to potentially fatal PE and the postthrombotic syndrome [2]. VTE is a major cause of morbidity and mortality not only in Western countries [3], as believed until recently, but also in Asia [4]. The standard treatment for acute VTE is anticoagulant therapy with fast-acting drugs such as unfractionated heparin (UFH), low molecular-weight heparin (LMWH) or the synthetic pentasaccharide fondaparinux, which all prevent thrombus extension and its consequences, followed by prophylaxis with vitamin K antagonists (VKAs) to prevent recurrence [5]. The fast-acting drugs are administered parenterally and VKAs orally [5]. Another condition for which anticoagulation is required is the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF) [6]. It has been estimated that AF affects 2.5 million individuals in the USA, including approximately 5% of those older than 65 years [7]. Finally, VKAs are used to prevent thromboembolism in patients with mechanical prosthetic heart valves [8]. A number of new drugs that may be suitable alternatives to the established agents, both for treatment and prophylaxis in all the above conditions, have recently become or will soon be available. The aim of this article is to review the current state of the art and to present expert opinion on what will be the practical impact for their application within the next few years. Need to develop new drugs Upon diagnosis, acute VTE must be promptly treated with fast-acting drugs to prevent thrombus extension. In this respect, UFH, LMWH or fondaparinux have proved to be highly effective and safe. However, the need for dose-adjustment (at least for UFH) based on laboratory tests and the need for parenteral administration (intravenous or subcutaneous infusion) make the use of these drugs challenging both for patients and physicians. Conversely, because of their oral route of administration, VKAs have been the agents of choice for secondary prophylaxis of VTE for the last 60 years. Vitamin K antagonists are also the drugs of choice for the primary prevention of stroke in patients with nonvalvular AF or prosthetic heart valves. Currently, AF is the most important indication for VKAs, accounting for more than 50% of all patients treated 554 ª 2012The Association for thepublication of the Journal of InternalMedicine

2 worldwide with these drugs. Patients treated with VKAs for any indication represent as many as 1.5% of the general population in Western countries, and thus the management of VKA treatment is a challenge for patients, their families and the healthcare systems. Although the organization of the management of VKA treatment has received special attention in many countries such as Italy, the Netherlands and the UK with the establishment of specialized anticoagulation clinics, most patients worldwide are still denied this life-saving therapy because of the perceived management difficulties and the risk of bleeding. Furthermore, although very effective, treatment with VKAs is complex, is associated with conspicuous burden for the healthcare systems and is highly demanding for patients. Vitamin K antagonists have several limitations that include a slow onset and offset of action, complex genetic control of their effect with polymorphisms leading to highly variable individual sensitivity and a narrow therapeutic window. In addition, metabolism of VKAs is affected by many factors, including diet, drugs, hepatic dysfunction, other co-morbid conditions and alcohol intake. As a result of these limitations, the dose response relationship of VKAs is unpredictable, and therefore frequent coagulation monitoring and dose-adjustment is needed to ensure efficacy of treatment and to minimize the risk of bleeding complications. Furthermore, the percentage of time spent in the therapeutic range might be inadequate. It was recently shown that the time within the therapeutic range was between 51.5% and 62.0% in community studies, rising to between 59.4% and 73.3% in randomized clinical trials [9]. These unsatisfactory results are of clinical relevance because an increased frequency of adverse events is associated with poor anticoagulation control [10]. New drugs The challenges posed by the established drugs (especially VKAs) prompted research to develop new anticoagulants (Fig. 1 and Table 1) that would be equally effective and safe, but not require laboratory monitoring for dose-adjustment. The results of the clinical trials carried out to date suggest that the new drugs will fulfil these expectations. However, definitive conclusions can only be drawn after they have been used to treat patients in real-life situations outside clinical trials. For instance, it is likely that laboratory control will be required to some extent in selected categories of patients. Initiation Thrombin generation Thrombin activity Coagulation Pathway X TF/VIIa Xa Va II IIa (thrombin) IXa VIIIa New Anticoagulant drugs Thrombin direct inhibitors (dabigatran) The drugs that are currently close to entering the market are dabigatran, rivaroxaban and apixaban. The aim of this article is to review the current situation with respect to the results of clinical trials for treatment of acute VTE and long-term prevention of recurrences as well as prevention of stroke in AF (Tables 2 and 3), and to discuss the methods that may be employed for laboratory control of these new agents (Tables 4 and 5). Dabigatran Dabigatran is an oral direct thrombin inhibitor (Fig. 1) that has undergone phase III, randomized, controlled clinical trials for both VTE and stroke prevention in AF. The characteristics of dabigatran are summarized in Table 1, and the main clinical trial results are summarized in Tables 2 and 3. Treatment of acute VTE: the RE-COVER study The RE-COVER study [11] was a randomized, double-blind, double-dummy, noninferiority trial that included a total of 2564 patients with acute VTE (encompassing proximal DVT and or PE). After initial treatment with parenteral anticoagulation therapy with LMWH or UFH (for a median of 9 days), patients were randomly assigned to receive dabigatran at a dose of 150 mg twice daily (b.i.d.) or dose-adjusted warfarin to achieve an international normalized ratio (INR) of The duration of treatment was 6 months. The primary analysis for efficacy, according to the intention-to-treat principle, was based on the composite end-point of symptomatic VTE or death associated with VTE in the 6 months after randomization. IX FXa direct inhibitors (rivaroxaban, apixaban) Fig. 1 Schematic representation of the coagulation cascade and coagulation factors targeted by the new drugs. TF, tissue factor. ª 2012 The Association for the Publicationof the Journal of InternalMedicine 555 Journal ofinternalmedicine, 2012, 271;

3 Dabigatran Rivaroxaban Apixaban Brand name Pradaxa Xarelto Eliquis Mechanism of action Direct, selective factor IIa inhibitor Direct, selective factor Xa inhibitor Direct, selective factor Xa inhibitor Prodrug Yes No No Time to Cmax 2[26] 2 4[30] 1 3[31] (hours) Half-life (hours) [26] 9 13 [30] 8 15 [31] Elimination 80% renal 20% biliary 1 3renal 1 3 renal (as inactive 25% renal 75% biliary metabolites) 1 3biliary Interactions P-glycoprotein P-glycoprotein and CYP3A4 P-glycoprotein (minimal) and CYP3A4 Effect of food Absorption Absorption Not reported delayed delayed Protein binding (%) Dosing b.i.d. o.d. b.i.d. Table 1 Main pharmacological characteristics of the new drugs Dabigatran and rivaroxaban are P-glycoprotein substrates. Amiodarone, verapamil and clarithromycin inhibit P-glycoprotein and therefore increase the anticoagulant effect of these factor IIa Xa inhibitors. For the safety analysis, bleeding was classified as major, according to Schulman and Kearon [12], or nonmajor clinically relevant. After central adjudication, occurrence of the primary outcome for efficacy was confirmed in 2.4% of all patients treated with dabigatran and in 2.1% of patients who received warfarin (time in therapeutic range 60%), establishing the noninferiority of dabigatran versus warfarin (P < 0.001). A major bleeding episode occurred in 1.6% and 1.9% of patients in the dabigatran and warfarin groups, respectively [hazard ratio (HR) 0.82; 95% confidence interval (CI), ]. The most frequent major bleeding event in the dabigatran group was gastrointestinal (n =9). Intracranial haemorrhage occurred in three patients treated with warfarin and in none receiving dabigatran. Major or clinically relevant nonmajor bleeding was detected in 5.6% of patients in the dabigatran group and in 8.8% in the warfarin group (HR, 0.63; 95% CI, ; P = 0.002). In total, 9.0% of patients in the dabigatran group and 6.8% in the warfarin group had an adverse event that led to discontinuation of the study drug (HR, 1.33; 95% CI, ; P =0.05). In conclusion, the results of the RE-COVER study showed that, after an initial few days of parenteral anticoagulation, treatment with dabigatran at the dose of 150 mg b.i.d. is noninferior for efficacy and at least as safe as warfarin at the usual INR level in subjects with acute VTE (Table 3). Secondary prevention of VTE: the RE-MEDY and RE-SONATE studies The preliminary results of these two studies have been presented at the XXIII Congress of the International Society on Thrombosis and Haemostasis, held in Kyoto in July In the double-blind, noninferiority RE-MEDY study [13], 2856 patients who had received 3 12 months of anticoagulant therapy after a VTE episode were randomly assigned to treatment with dabigatran 150 mg b.i.d. or warfarin (INR ) for an additional period of 6 36 months. Safety outcomes were bleeding events, acute coronary syndromes and other adverse events. Recurrent symptomatic VTE occurred in 1.8% and 1.3% of patients treated with dabigatran and warfarin, respectively (HR 1.44; 95% CI ; P = 0.03 for noninferiority). Major bleeding occurred in 0.9% and 1.8% of dabigatran- and warfarin-treated patients, respectively (HR 0.52; 95% CI, ). Any bleeding occurred in 19% of patients receiving 556 ª 2012The Association for thepublication of the Journal of InternalMedicine Journal of InternalMedicine, 2012, 271;

4 Table 2 Phase III clinical trials to assess the efficacy and safety of treatment with the new drugs Study Clinical condition Reference Dabigatran RE-COVER Treatment of acute VTE [11] RE-MEDY and RE-SONATE Secondary prevention of VTE [13] RE-LY Rivaroxaban EINSTEIN programme Rocket AF Apixaban ARISTOTLE AVERROES Amplify VTE programme Treatment of patients with nonvalvular AF [15] Treatment of acute DVT [19] Stroke prevention in patients with nonvalvular AF Stroke prevention in patients with nonvalvular AF Stroke prevention in patients with nonvalvular AF Treatment of acute VTE (AMPLIFY CV ) Secondary prevention of VTE (AMPLIFY-EXT CV ) [20] [21] [25] (Both studies are ongoing) VTE, venous thromboembolism. AF, atrial fibrillation. DVT, deep vein thrombosis. treatment with dabigatran and in 26% of those receiving warfarin (HR 0.71; 95% CI, ). Higher rates of acute coronary syndromes were observed in patients treated with dabigatran compared with those treated with warfarin (0.9% vs. 0.2%; P = 0.02). It was concluded that dabigatran was as effective as warfarin for the extended treatment of VTE; dabigatran was associated with a reduced risk of bleeding but an increased incidence of acute coronary events (Table 3). In the double-blind RE-SONATE study [14], 1343 patients with VTE who had completed 6 18 months of anticoagulant therapy were randomly assigned to receive dabigatran 150 mg b.i.d. or placebo for a further 6 months. Patients with a clear indication to continue anticoagulation were not eligible. Recurrent VTE was observed in 0.4% of patients treated with dabigatran and 5.6% of those treated with placebo (HR 0.08; 95% CI ; P < ). There were two major bleeding episodes (both gastrointestinal; 0.39%) in the dabigatran group and none in the placebo group. Clinically, relevant nonmajor bleeding occurred in 5.3% and 1.8% of patients treated with dabigatran and placebo, respectively (HR 2.9; 95% CI, ; P = 0.001). The rate of cardiovascular events was not different in the two groups. It was concluded that extended treatment with dabigatran was highly effective in reducing the rate of VTE recurrences compared with placebo, and was associated with only a low risk of major bleeding (Table 3). Treatment of patients with nonvalvular AF: the RE-LY study The RE-LY study was a noninferiority trial in which patients with AF were randomly assigned to two fixed doses of dabigatran (110 mg or 150 mg b.i.d.), administered in a blinded manner, or to openlabel use of warfarin [15]. The median duration of follow-up was 2 years. The primary efficacy outcome was stroke or systemic embolism, and the main outcome for safety was major bleeding. Amongst the major bleeding episodes, other events that were considered life-threatening were symptomatic intracranial bleeding, decrease in haemoglobin level of at least 5gdL )1, haemorrhage requiring transfusion of at least four units of blood or inotropic agents or events necessitating surgery. With regard to the study population, the mean patient age was 71 years, and 63.6% were men. Half of all patients had received long-term therapy with VKAs. The mean CHADS2 score was 2.1. Aspirin was used during the treatment period in about 20% of patients in all the three groups. The mean percentage of time within the therapeutic range for warfarin (INR ) was 64%. Stroke or systemic embolism occurred at a rate of 1.69% per year in patients receiving warfarin and 1.53% and 1.11% per year, respectively, in those treated with 110 or 150 mg dabigatran. Both doses of dabigatran were noninferior to warfarin (P < 0.001), but the latter was also superior (RR versus warfarin 0.66; 95% CI ; P < 0.001). Amongst other outcomes, the rate of myocardial infarction was found to be significantly higher in the 150 mg dabigatran group (0.74% per year) than in the warfarin group (0.53% per year; RR 1.38; 95% CI, ; P = 0.048). However, after a subsequent revision of the database, new events were detected, adjudicated ª 2012 The Association for the Publicationof the Journal of InternalMedicine 557 Journal ofinternalmedicine, 2012, 271;

5 Table 3 Main conclusions of phase III clinical trials Study Conclusion Reference Dabigatran RECO-VER (treatment of acute VTE) After parenteral anticoagulation, dabigatran 150 mg b.i.d is noninferior for efficacy and at least as safe as VKAs [11, 12] RE-MEDY (secondary prevention of VTE) RE-SONATE (secondary prevention of VTE) RE-LY (stroke prevention in AF) Rivaroxaban Acute DVT Study (treatment of DVT) Acute PE Study (treatment of PE) Continued Treatment Study (secondary prevention of VTE) ROCKET AF (stroke prevention in AF) Apixaban ARISTOTLE (stroke prevention in AF) AVERROES (stroke prevention in AF) Dabigatran is as effective as VKAs in the extended treatment of VTE. It is associated with a reduced risk of bleeding, but an increased incidence of acute coronary events Extended treatment with dabigatran is highly effective in reducing the rate of recurrence compared to placebo and is associated with a low risk of major bleeding Dabigatran 110 mg b.i.d. is as effective as VKAs with lower rates of major bleeding. Dabigatran 150 mg b.i.d. is associated with lower rates of stroke and systemic embolism, but similar rates of major haemorrhage. Dabigatran 110 and 150 mg are associated with lower rates of ICH than VKAs Rivaroxaban 15 mg b.i.d. for the first 3 weeks, followed by 20 mg o.d. thereafter provides an effective and safe, single-drug approach to the initial and continued treatment of VTE Rivaroxaban 20 (or 15) mg o.d. is noninferior to VKAs in patients with moderate-to-high risk of stroke. There is no difference in rates of major and clinically relevant nonmajor bleeding between treatments. ICH occurs less frequently with rivaroxaban than VKAs Apixaban 5 (or 2.5) mg b.i.d. is superior to VKAs and is associated with less bleeding and lower mortality. Apixaban 5 (or 2.5) mg is associated with a lower rate of ICH than VKAs Apixaban 5 (or 2.5) mg b.i.d. given to patients who cannot take VKAs is more effective than aspirin, without increasing the risk ofmajorbleedingorich [13] [14] [15, 16] [17] (Study ongoing) VTE, venous thromboembolism. AF, atrial fibrillation. DVT, deep vein thrombosis. PE, pulmonary embolism. ICH, intracranial haemorrhage. VKA, vitamin K antagonist. [17] [18] [19] [23] in a blinded fashion and in accordance with the study protocol, and the significant difference regarding the rates of myocardial infarction was no longer evident [16]. After a further recent revision of the RE-LY results, it was found that there was a nonsignificant increase in myocardial infarction with dabigatran compared with warfarin and that other clinical events related to myocardial ischaemia were not increased [17]. However, it should be noted that treatment with dabigatran was found to be associated with a significantly increased odds ratio (1.33; 95% CI ) for myocardial infarction or acute coronary syndrome in a recent meta-analysis of seven randomized trials [18]. 558 ª 2012The Association for thepublication of the Journal of InternalMedicine Journal of InternalMedicine, 2012, 271;

6 Table 4 Situations that may require laboratory control of the new drugs Emergency presentation with thrombotic or haemorrhagic events Need for immediate reversal of anticoagulation Previously unrecognized renal failure Liver failure Suspicion of or known interaction with other drugs With regard to safety, the rate of major bleeding was 3.36% per year in the warfarin group, 2.71% per year in the 110 mg dabigatran group (RR 0.80; 95% CI, ; P = 0.003) and 3.11% per year in the 150 mg dabigatran group (RR 0.93; 95% CI, ; P = 0.31). Of particular interest are the lower rates of intracranial bleeding recorded in patients who received dabigatran: 0.74% per year in the warfarin group and 0.23% and 0.30% per year in the 110 mg and 150 mg dabigatran groups, with an RR of 0.31 and 0.40 (both P < 0.001), respectively. The rate of major gastrointestinal bleeding was significantly higher with dabigatran at the 150 mg dose (1.51% per year) than with warfarin (1.02% per year; P < 0.001). With regard to other adverse events, dyspepsia was the most frequent in the dabigatran groups (>11% with either dose) and significantly more frequent than in the warfarin group (P <0.001). Liver enzymes were not abnormally elevated more frequently with dabigatran, at either dose, than with warfarin. In conclusion, the RE-LY study performed in patients with AF confirmed that, compared with standard treatment with warfarin, dabigatran at a dose of 110 mg b.i.d. was equally effective, but was associated with significantly lower rates of major bleeding, including intracranial bleeding. At a dose of 150 mg b.i.d., dabigatran was associated with lower rates of stroke, systemic embolism and intracranial bleeding, but similar rates of other major haemorrhage (Table 3). Rivaroxaban Rivaroxaban is an oral direct factor Xa inhibitor (Fig. 1), and phase III, randomized, controlled clinical trials have been conducted for both VTE and stroke prevention in AF. The main characteristics of rivaroxaban are summarized in Table 1, and the clinical trials results are summarized in Tables 2 and 3. Treatment of acute DVT: the EINSTEIN programme The EINSTEIN programme consists of three randomized trials of rivaroxaban: the Acute DVT Study and the Acute PE Study, for the acute treatment of patients with symptomatic DVT or PE, respectively, and the Continued Treatment Study for prolonged treatment of patients after therapy for acute DVT or PE. The results of the Acute DVT Study and Continued Treatment Study have been recently reported by Bauersachs et al. [19], whereas the Acute PE Study is ongoing. The Acute DVT Study was an open-label, event-driven, randomized, noninferiority trial that compared oral rivaroxaban alone [15 mg b.i.d. for 3 weeks, followed by 20 mg once daily (o.d.)] with standard anticoagulation treatment (subcutaneous enoxaparin followed by VKA therapy to a target INR of ) for 3, 6 or 12 months in patients with acute, symptomatic DVT and without symptomatic PE. After the com- Table 5 Main laboratory tests to assess the anticoagulant effect of the new drugs Test Characteristics Reference Dabigatran Prothrombin time Linear dose response, not very responsive to increasing dosage [26] Activated partial thromboplastin time Nonlinear dose response, adequately responsive to increasing dosage [26] Dilute thrombin time Linear dose response, adequately responsive to increasing dosage [26] Ecarin clotting time Linear dose response, adequately responsive to increasing dosage [26] Rivaroxaban Prothrombin time Linear dose response, adequately responsive to increasing dosage [28] Activated partial thromboplastin time Linear dose response, adequately responsive to increasing dosage [28] Anti-factor Xa activity Linear dose response, adequately responsive to increasing dosage [27] ª 2012 The Association for the Publicationof the Journal of InternalMedicine 559 Journal ofinternalmedicine, 2012, 271;

7 pletion of 6 12 months of treatment, patients with DVT or PE were included in the Continued Treatment Study, a double-blind, randomized, superiority study that compared rivaroxaban alone (20 mg o.d.) with placebo for an additional 6 or 12 months. The primary efficacy outcome for both studies was recurrent VTE. The principal safety outcome was major bleeding or clinically relevant nonmajor bleeding in the initial treatment study and major bleeding in the study of continued treatment. In the Acute DVT Study, which included 3449 patients, the primary efficacy outcome occurred in 2.1% of patients who received rivaroxaban and in 3.0% of those who received LMWH+VKAs; time in the therapeutic range for warfarin was 57.7% and the HR was 0.68 (95% CI ; P < for noninferiority). With regard to safety, major or clinically relevant nonmajor bleeding occurred in 8.1% of patients treated with either rivaroxaban or standard therapy (HR for rivaroxaban, 0.97; 95% CI, ; P = 0.77). The outcome of a net clinical benefit occurred in 2.9% of patients in the rivaroxaban group and 4.2% in the standard therapy group (HR 0.67; 95% CI, ; P =0.03). There were no differences in other adverse events between the two groups. A total of 1197 patients were enrolled in the Continued Treatment Study. Outcome events occurred in 1.3% of patients in the rivaroxaban group and 7.1% in the placebo group (HR 0.18; 95% CI, ; P < 0.001; relative risk reduction 82%). The principal safety outcome of major bleeding occurred in four patients (0.7%) in the rivaroxaban group and in none in the placebo group (P = 0.11). However, major or clinically relevant nonmajor bleeding occurred in 6.0% and 1.2% in the rivaroxaban and placebo groups, respectively (P < 0.001). From the results of both studies it appears that oral rivaroxaban, at a dose of 15 mg b.i.d. for the first 3 weeks followed by 20 mg o.d. thereafter, can provide an effective, safe, single-drug approach to the initial and continued treatment of VTE (Table 3). Treatment of patients with nonvalvular AF: the ROCKET AF study The ROCKET AF study was a multicentre, randomized, double-blind, double-dummy, event-driven trial in which patients with AF were randomly assigned to receive fixed-dose rivaroxaban 20 mg o.d. (or 15 mg o.d. in patients with a creatinine clearance of 30 to 49 ml min )1 ) or adjusted-dose warfarin (target INR ) [20]. The median duration of exposure to treatment was 590 days, and the median follow-up period was 707 days. The primary efficacy end-point was the composite of stroke (either ischaemic or haemorrhagic) and systemic embolism. The principal safety end-point was a composite of major and nonmajor clinically relevant bleeding events. The median patient age was 73 years and 60.3% of participants were male patients. Patients were at moderate-to-high risk of stroke; only those with a CHADS2 score of 2 (mean score of 3.5) were included in the study. Previous use of VKAs was reported by 62.4% of patients and about one-third of the patients also took aspirin at some time during the study. In warfarin-treated patients, INR values were within the therapeutic range, an average of 55% of the time. In the per-protocol population, primary outcome events occurred at a rate of 1.7% per year in the rivaroxaban group and 2.2% per year in the warfarin group (HR 0.79; 95% CI ; P <0.001fornoninferiority). In the intention-to-treat analysis, primary efficacy events occurred at a rate of 2.1% per year in rivaroxaban-treated patients and 2.4% per year in the warfarin group (HR 0.88; 95% CI ; P <0.001fornoninferiorityandP =0.12for superiority). With regard to safety, the rates of major bleeding were not different in the rivaroxaban- and warfarin-treated patients (3.6% and 3.4%, respectively); the rates of major and clinically relevant nonmajor bleeding were also similar in the two groups (14.9% and 14.5% per year). Intracranial haemorrhage occurred less frequently in rivaroxaban-treated patients than in those receiving warfarin (0.5% vs. 0.7% per year, respectively; HR 0.67; CI ; P = 0.02). The effect of rivaroxaban when compared to warfarin did not differ across quartiles of the percentage of time of INR within the therapeutic range according to study centre. There were no differences in serious adverse events between the two treatment groups. In conclusion, the study showed that a fixed dose of rivaroxaban given on a daily basis was noninferior to adjusted-dose warfarin in patients with nonvalvular AF at moderate-to-high risk of stroke. There were no significant differences in rates of major and clinically relevant nonmajor bleeding between the two treatments. Intracranial bleeding occurred less frequently in rivaroxaban-treated patients (Table 3). 560 ª 2012The Association for thepublication of the Journal of InternalMedicine Journal of InternalMedicine, 2012, 271;

8 Apixaban Apixaban is an oral direct factor Xa inhibitor (Fig. 1) that has undergone phase III randomized clinical trials for stroke prevention in AF. The main characteristics of apixaban are summarized in Table 1, and the results from these clinical trials are summarized in Tables 2 and 3. Treatment of patients with nonvalvular AF: the ARISTOTLE study The ARISTOTLE study was a double-blind, doubledummy study in which patients with nonvalvular AF were randomly assigned to treatment with apixaban 5 mg b.i.d. or dose-adjusted warfarin (INR ) [21]. A lower apixaban dose (2.5 mg b.i.d.) was used in patients with at least two of the following criteria: age 80 years, body weight 60 kg and serum creatinine level 1.5 mg dl )1.Themedianfollowup duration was 1.8 years. The median age of study participants was 70 years; 35.3% were women and the mean CHADS2 score was 2.1. Approximately, 57% of patients had previously received VKA treatment. The median time spent within the therapeutic INR range in the warfarin group was 66.0%. Primary outcome events (stroke or systemic embolism) occurred at a rate of 1.27% per year in the apixaban group and 1.60% per year in the warfarin group (HR 0.79; 95%; CI ; P <0.001fornoninferiority and P = 0.01 for superiority). The rates of death from cardiovascular and noncardiovascular causes and of myocardial infarction were lower (although not statistically significantly different) in the apixaban group compared with the warfarin group. Major bleeding occurred at a rate of 2.13% per year in the apixaban group and 3.09% per year in the warfarin group (HR 0.69; 95% CI, ; P < 0.001). The rate of intracranial haemorrhage was 0.33% per year in the apixaban group and 0.80% per year in the warfarin group (HR 0.42; 95% CI ; P <0.001). Furthermore, the rate of any bleeding was 25.8% per year in the warfarin group and 18.1% per year in the apixaban group, with an absolute reduction of 7.7 percentage points (P < 0.001). The overall rates of serious adverse events were not different in the two treatment groups. In conclusion, the study showed that a fixed dose of apixaban (given b.i.d.) in patients with AF was superior to warfarin in preventing stroke or systemic embolism and was associated with less bleeding (including intracranial bleeding) and lower mortality (Table 3). Apixaban in patients with AF: the AVERROES study It is well known that VKA therapy is effective for prevention of cardioembolism in patients with AF. However, its use is limited by many factors and at least one-third of AF patients who are at risk of complications does not receive VKA therapy, or discontinue treatment [22]. Despite the fact that aspirin is not, or only slightly, effective [23] in reducing thromboembolic complications in these patients, it is largely used to treat those, especially the elderly people, who for various reasons are not suitable for VKA therapy [24]. The AVERROES study [25] was designed to determine the efficacy and safety of apixaban at a dose of 5 mg b.i.d. (2.5 mg in 6% of patients), compared with aspirin at a dose of 81 to 324 mg o.d., for the treatment of patients with nonvalvular AF for whom VKA therapy was considered unsuitable. Of the 5599 patients enrolled, 40% had previously received but discontinued VKA treatment, 42% of them because the INR could not be maintained in the therapeutic range. The treating physician had established that INR measurements could not be regularly obtained in 43% of the other patients enrolled. VKA therapy was considered to be unsuitable for 21% of patients because the risk of stroke was only moderate (CHADS2 score of 1). In addition, 15% of patients did not want to take VKAs. The mean duration of follow-up was 1.1 years. The rates of primary outcome events were 1.6% per year in patients treated with apixaban and 3.7% per year in those assigned to aspirin (HR 0.45, 95% CI ; P < 0.001). The rate of major bleeding was 1.4% per year in patients taking apixaban and 1.2% per year amongst those taking aspirin (HR 1.13; 95% CI, ; P = 0.57). An intracerebral haemorrhage occurred in six and nine patients receiving apixaban and aspirin, respectively. In an on-treatment analysis, whilst patients were receiving the study treatment, major bleeding events occurred at a rate of 1.4% and 0.9% per year in the apixaban and aspirin groups, respectively (HR 1.54; 95% CI, ; P = 0.07). Serious adverse events occurred significantly less frequently in the apixaban than in the aspirin group (22% vs. 27%; P <0.001). In conclusion, the study showed that, in comparison with aspirin, apixaban substantially reduced the risk of thromboembolic complications in patients with AF for whom VKA therapy is unsuitable, without increasing the risk of major or intracranial bleeding (Table 3). ª 2012 The Association for the Publicationof the Journal of InternalMedicine 561 Journal ofinternalmedicine, 2012, 271;

9 Treatment of VTE: the AMPLIFY programme Two clinical trials are ongoing to assess the efficacy and safety of apixaban in subjects with VTE. The double-blind, double-dummy AMPLIFY CV study is enrolling patients with acute DVT and or PE who are randomly assigned to receive apixaban 5 mg b.i.d. or warfarin (INR ) for 6 months. The enrolment of 5400 patients is expected to be complete in July For the AMPLIFY-EXT CV , enrolment was completed in July The study included patients with a recent VTE episode who received a first standard anticoagulation course for 6 12 months. After this period, patients were randomly assigned to receive placebo or apixaban for 1 year; those treated with apixaban were further randomly assigned to receive 2.5 or 5 mg b.i.d. apixaban in a double-blind fashion. The follow-up of patients is ongoing. Laboratory control of new drugs Clinical trials with dabigatran, rivaroxaban and apixaban have been designed with a fixed dosage without any laboratory control. Indeed, these drugs have proved to be effective and safe for the investigated conditions (see above) and, therefore, strict laboratory control and or dose adjustment are not required [24, 25]. However, it should be recognized that patients enrolled in clinical trials are highly selected, and therefore it is possible that they do not represent the general population encountered in the real-life clinical situation. Thus, laboratory monitoring might be needed, at least to some extent. Although experience is still limited, as these drugs are not yet used on a large scale, we can start to consider the most appropriate strategy for laboratory control of these new drugs on the basis of current knowledge [26]. Situations requiring laboratory control The following situations may require laboratory control. (i) Emergency presentation with thrombotic or haemorrhagic events. The treating physician may need to know whether the adverse events are due to over- or under-dosage of the drug. (ii) Need for immediate reversal of anticoagulation. Laboratory control may be needed to judge objectively whether or not reversal has been achieved. (iii) Previously unrecognized renal failure. The kidney is the main route of excretion for some of these drugs. Therefore, laboratory control may be needed to identify drug accumulation in cases of renal failure. (iv) Liver failure. No information is currently available on the effect of these drugs in this setting as the presence of chronic liver failure has been one of the exclusion criteria for most of the clinical trials so far carried out. (v) Suspicion of or known interaction with other drugs. Although very few interactions have hitherto been reported, the possibility of drug interactions cannot be excluded apriori; therefore, laboratory control may occasionally be needed in this situation (Table 4). Potentially useful tests On the basis of limited experience, it appears that most of the global and some specific tests can be used to evaluate the anticoagulant effect of the new drugs (Table 5). Dabigatran To date, the following tests have been evaluated with regard to dabigatran. (i) Activated partial thromboplastin time (APTT). This test showed a relatively poor dose response linearity and an intermediate responsiveness to increasing dose [26]. Different results have been obtained depending on the reagents used. Hence, it is anticipated that standardization across laboratories will be difficult. As a consequence, management of patients cannot be generalized on the basis of the test results. (ii) Thrombin clotting time (TT). Preliminary evaluations have shown that this test has excellent linearity, but excessive responsiveness to increasing dose [26]. It is anticipated that standardization across laboratories will be an issue. (iii) Prothrombin Time (PT). Good linearity but poor responsiveness has been reported for PT [26]; it is also anticipated that standardization will be difficult. (iv) Ecarin clotting time (ECT). This test has shown good linearity and excellent responsiveness. However, standardization can be a problem due to the type concentration of phospholipids and purity of the snake venoms used for testing. (v) Others. In theory the thrombin generation test could be useful; however, at present the method is too complex for daily routine use. Rivaroxaban and apixaban The following tests may be useful to evaluate the anticoagulant effects of rivaroxaban and apixaban. Most of the currently available information focuses on rivaroxaban; however, it is likely that results will also be valid for apixaban. (i) Anti-factor Xa activity. In theory this should be the test of choice [27]; however, it is not readily available in an emergency. As a result of the 562 ª 2012The Association for thepublication of the Journal of InternalMedicine Journal of InternalMedicine, 2012, 271;

10 large between-reagent variability, it is anticipated that standardization will be difficult to achieve. (ii) PT. Good linearity and responsiveness have been shown with PT [28]. Results are dependent on the type of thromboplastin used for testing, but evidence has been provided that standardization across reagents is feasible by employing an international sensitivity index (ISI) based on plasma supplemented with increasing doses of rivaroxaban [29]. This index (ISIrivaroxaban) was successfully used to convert PT ratio into INR calibrated for rivaroxaban (INR-rivaroxaban) [29], which proved effective in minimizing between-thromboplastin variability [29]. (iii) APTT. This test has excellent linearity, but poor responsiveness to increasing dose [28], and standardization will be difficult. (iv) HepTest. Good linearity and excellent responsiveness have been shown [28] but standardization could be an issue. (v) Dilute Russell viper venom test. This test also has good linearity and responsiveness [28]. Standardization might be an issue because of the variety of phospholipids and purity of snake venom used for testing. (vi) Others. Other tests, for example using portable coagulometers with test strips calibrated in terms of INR valid for patients on VKAs and thrombin generation tests, have been proposed [28] but their advantages compared with previous tests have not been investigated. Recommended tests Based on the aforementioned considerations and the present limited experience, we recommend ECT or dilute TT for dabigatran and the PT for rivaroxaban and apixaban. The ECT and dilute TT are simple, readily available tests that can be run using a standard coagulometer; the PT is also a simple and readily available test. Furthermore, we recommend that results for these tests should be expressed as the ratio (patient normal) of the clotting time. In particular, PT results should be expressed as the clotting time ratio (patient normal), or INR valid for this drug. Expression of the results as an INR valid for patients on VKAs is strongly discouraged as it was shown that this dramatically increases the between-reagent variability [29]. Future directions Until now, VKAs have been the only oral agents available for long-term anticoagulation and are therefore widely used for prevention of thromboembolic complications and for treatment in many clinical conditions that involve a large and increasing number of patients. However, according to both patients and physicians, for many years there has been a real need for a substantial improvement in anticoagulant treatment with new drugs, possibly free from some of the limitations of VKAs and heparins. As shown in this review, the oral direct thrombin or factor Xa inhibitors are in the advanced phase of clinical investigation with a number of phase III clinical trials having demonstrated their efficacy and safety for prolonged treatments. One of these drugs, dabigatran, is already available for chronic clinical use in some countries, whereas others are expected to become available soon for stroke prevention in AF patients and for treatment of VTE. We believe that the use of these new drugs is an important step towards an easier, effective and safe long-term anticoagulant treatment, which will enable effective antithrombotic treatment even in those patients in whom an adequate anticoagulation is currently denied due to the limitations of VKAs. However, some aspects of the use of these new drugs require careful consideration before they are introduced for broad clinical use. Some of these drugs (although to different degrees) are excreted via the kidney (see Table 1). This indicates a potential risk of drug accumulation in patients with renal failure, suggesting the need for dosage reduction and or therapeutic monitoring. This is important especially in the elderly people in whom close clinical control and frequent renal function assessment is highly advisable. Although lower with the new drugs than with VKAs, there is still some risk of drug drug interactions. Furthermore, previous experience with a different agent (ximelagatran) suggests that it is advisable to collect long-term data on the safety of these drugs, For instance, clearance of apixaban is mainly hepatic (@ 75%) and caution should be used in patients with liver dysfunction. Whichever drug is used, good patient compliance is of paramount importance for an effective and safe anticoagulant treatment. Poor compliance, however, can be even more serious with the new drugs than with VKAs. Indeed, whilst the anticoagulant effect of VKAs lasts for several days, the relatively rapid offset of action of the new drugs may result in a rapid and complete lack of anticoagulant protection in patients who forget their medication for only 1 or 2 consecutive days. Furthermore, in contrast to VKA therapy, where an erratic compliance to the treatment can be detected in a timely manner due to repeated clinic visits and INR determinations, the absence of periodic visits with the new drugs may reduce the attention to ad- ª 2012 The Association for the Publicationof the Journal of InternalMedicine 563 Journal ofinternalmedicine, 2012, 271;

11 here to therapy. The use of the new drugs requires maximum effort to ensure adherence to treatment and to develop interventions to maintain good compliance during long-term therapy. The new drugs do not need routine coagulation monitoring, which is an important and favourable characteristic. However, there are instances when the drug effect may need to be evaluated (see Table 4). Potential differences between the results obtained in clinical trials and the effects of the new drugs in the real-life clinical situation should be carefully assessed with specifically designed postmarketing studies. The phase III clinical studies of these drugs, in general, included only highly selected patients and important groups were excluded, particularly the elderly people or those with chronic co-morbid conditions (especially cancer and renal or cardiac failure) or intercurrent illnesses. In the real-life situation, one must address the needs of these patients, and an assessment of the benefit risk ratio associated with the new drugs is essential. Specifically, designed postmarketing, long-term studies are therefore needed. Finally, we believe there is a need for a change in the role and activity of anticoagulation clinics that manage patients requiring long-term VKA therapy. In the future their activity should be more focused on clinical aspects, including education of or information for patients for the optimal use of the new drugs, the best possible compliance to treatment and periodic clinical surveillance of patients and their management in case of complications during treatment. Moreover, anticoagulation clinics are ideal for performing collaborative studies to assess the effectiveness and safety of the new drugs in comparison with VKAs. Conclusions New direct thrombin or factor Xa inhibitors are now becoming available. These drugs have the potential to overcome some of the problems associated with the older antithrombotic agents. They can be administered orally, have a relatively short half-life, acceptable therapeutic window, predictable dose response relationship and no need for regular laboratory monitoring and dose-adjustment. As a result of all these characteristics, they are much more manageable and appealing than heparins or VKAs for patients and physicians. Following the completion of phase III clinical trials and the recent approval by the US Food and Drug Administration as well as other regulatory agencies, they can be prescribed for treatment and prophylaxis of thrombotic events, thus opening a new era in antithrombotic treatment for millions of patients worldwide. However, because results from clinical trials cannot be easily generalized to the real-life situation, these new drugs must undergo close scrutiny in phase IV clinical trials to establish their efficacy and safety. 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